A Tissue Virus Microenvironment with Activated Stress Responses Underlies Durable SIV Persistence

Area of Science:

• Virology
• Immunology
• Systems Biology

Background:

• HIV persistence during antiretroviral therapy (ART) is a major obstacle to cure, with reservoirs primarily located in gut-associated lymphoid tissues (GALT).
• Understanding the tissue microenvironment is critical for elucidating reservoir durability and viral rebound dynamics.

Purpose of the Study:

• To define the spatially organized viral microenvironment (VME) that sustains persistent HIV reservoirs.
• To compare the characteristics of transient versus persistent reservoirs following analytical treatment interruption (ATI).

Main Methods:

• ImmunoPET/CT-guided sampling of SIV-infected rhesus macaques.
• Spatial transcriptomics to analyze tissue sites of viral production.
• Machine learning to identify predictive pathways of viral density.

Main Results:

• Persistent reservoirs arise from transcriptionally active foci in the gut mucosa, characterized by stress response, metabolic rewiring, and cellular senescence.
• Transient reservoirs exhibit enhanced translational and metabolic activity within immune-active environments.
• Machine learning identified stress adaptation, hypoxia, and metabolic rewiring as key predictors of viral density in persistent VMEs, converging with tumor microenvironment pathways.

Conclusions:

• The viral microenvironment (VME) is a critical determinant of HIV reservoir persistence, integrating immune regulation, tissue remodeling, and translational control.
• Effective HIV cure strategies must target VME-supportive functions alongside infected cells.
• Findings highlight the integrated stress response (ISR) activation at sites of viral production.